Water-soluble eye drop

ABSTRACT

A water-soluble eye drop comprising (a) at least one selected from carteolol and an acid addition salt thereof, (b) at least one acrylic polymer selected from a straight-chain type polyacrylic acid and a pharmaceutically acceptable water-soluble salt thereof, and (c) at least one selected from a water-soluble alkali metal salt and a water-soluble amine. The water soluble eye drop has a remarkably long duration time of drug efficacy, and is superior in intraocular pressure inhibition action and is effective for treatment of glaucoma.

TECHNICAL FIELD

The present invention relates to a water-soluble eye drop. Moreparticularly, it relates to a water-soluble eye drop which has aremarkably long duration time of drug efficacy, and which is superior inan intraocular pressure inhibition action and is effective for treatmentof glaucoma.

BACKGROUND ART

It has been well known that a carbostyryl derivative represented by theformula (1):

wherein R represents a tert-butyl group, or an acid addition saltthereof is a compound which is effective as a remedy for glaucoma (U.S.Pat. No. 4,309,432). The compound represented by the above formula (1)is referred to as carteolol.

On the other hand, an eye drop or an ophthalmic ointment is often usedas the eye drop.

In case of the eye drop, since a base is usually purified water, it isdifficult to adhere the eye drop onto the cornea in the case of droppingit in the eyes. Furthermore, it is impossible to avoid that the eye dropis diluted with lacrimal fluid and falls from the eyes. Accordingly, itwas difficult for a conventional eye drop to sufficiently retain a drugin the eye drop in the eyes.

Furthermore, the ophthalmic ointment is prepared by adding liquidparaffin, purified lanolin or the like to petrolatum as a base. Such anophthalmic ointment is liable to be discharged from the eyes by means oflacrimal fluid because of its poor hydrophilicity. Therefore, there issuch a drawback that the opthalimic ointment is not sufficiently adheredonto the cornea and ophthalmic mucosa and, as a result, the amount ofthe drug in the ophthalmic ointment, which arrives the affected part andis absorbed, is small. The ophthalmic ointment also has a drawback thatan unpleasant feel arises in the eyes after applying it because ofoiliness of an oily base.

To solve the above drawbacks of the conventional eye drop and ophthalmicointment, British Patent No. 2,007,091 corresponding to Japanese PatentLaid-Open Publication No. 67021/1979 suggests a gelled eye drop. Thegelled eye drop described in said publication is an eye drop prepared bymixing an aqueous crosslinked type polyacrylic acid solution with awater-soluble basic substance and a drug for eye drop, which has the pHof 5 to 8 and the viscosity of 1,000 to 100,000 centipoise at 20° C.

However, such a gelled eye drop is insufficient in duration time of drugefficacy, and is inferior in intraocular pressure inhibition action.Furthermore, the gelled eye drop is also insufficient in ease ofhandling and affinity to the eyes (feeling in the case of dropping it inthe eyes). Accordingly, it is difficult to use such a gelled eye drop asan eye drop which is particularly effective for treatment of glaucomarequiring the control of the intraocular pressure.

SUMMARY OF THE INVENTION

To develop a water-soluble eye drop having no drawbacks described above,the present inventors have intensively studied. As a result, they havefound that a water-soluble eye drop comprising the following component(a), component (b) and component (c) can be used as a desiredwater-soluble eye drop having no drawbacks described above.

That is, the present invention relates to a water-soluble eye dropcomprising (a) at least one selected from carteolol and an acid additionsalt thereof, (b) at least one acrylic polymer selected from astraight-chain type polyacrylic acid and a pharmaceutically acceptablewater-soluble salt thereof, and (c) at least one selected from awater-soluble alkali metal salt and a water-soluble amine.

Although a base is purified water, the eye drop of the present inventionis easily applied onto the cornea in the case of dropping it in the eyesand is not likely to fall from the eyes even if the eye drop is dilutedwith lacrimal fluid. Accordingly, according to the eye drop of thepresent invention, a drug component in the eye drop in the eye drop canbe retained sufficiently in the eyes.

The water-soluble eye drop of the present invention has a remarkablylong duration time of drug efficacy, and is superior in intraocularpressure inhibition action. Accordingly, the water-soluble eye drop ofthe present invention is an eye drop which is particularly effective fortreatment of glaucoma requiring the control of the intraocular pressure.

Furthermore, the water-soluble eye drop of the present invention issatisfactory in ease of handling and affinity to the eyes (feeling inthe case of dropping it in the eyes).

DETAILED DESCRIPTION OF THE INVENTION

The water-soluble eye drop of the present invention includes embodimentsdescribed hereinafter.

1) A water-soluble eye drop comprising (a) at least one selected fromcarteolol and an acid addition salt thereof, (b) at least one acrylicpolymer selected from a straight-chain type polyacrylic acid and apharmaceutically acceptable water-soluble salt thereof, and (c) at leastone selected from a water-soluble alkali metal salt and a water-solubleamine.

2) The water-soluble eye drop according to the above item 1), whereinthe component (a) and the component (b) are contained in the amount ofabout 0.1 to 5% by weight and the amount of about 0.3 to 10% by weight,respectively, and the concentration of the component (c) is from-about10 to 140 mmol.

3) The water-soluble eye drop according to the above item 2), whereinthe pH of the water-soluble eye drop is from about 4 to 10 and theviscosity at 25° C. of the water-soluble eye drop is from about 5 to 100centipoise and, furthermore, the viscosity-average molecular weight ofthe acrylic polymer of the component (b) is from about 100,000 to3,000,000.

4) The water-soluble eye drop according to the above item 3), whereinthe pH of the water-soluble eye drop is from about 5 to 9 and theviscosity at 25° C. of the water-soluble eye drop is from about 10 to 70centipoise and, furthermore, the viscosity-average molecular weight ofthe acrylic polymer of the component (b) is from about 2,000,000 to3,000,000.

5) The water-soluble eye drop according to the above item 2), whereinthe component (a) and the component (b) are contained in the amount ofabout 0.5 to 3% by weight and the amount of about 0.3 to 0.5% by weight,respectively, and the concentration of the component (c) is from about30 to 120 mmol.

6) The water-soluble eye drop according to the above item 5), whereinthe pH of the water-soluble eye drop is from about 4 to 10 and theviscosity at 25° C. of the water-soluble eye drop is from about 5 to 100centipoise and, furthermore, the viscosity-average molecular weight ofthe acrylic polymer of the component (b) is from about 100,000 to3,000,000.

7) The water-soluble eye drop according to the above item 5), whereinthe pH of the water-soluble eye drop is from about 5 to 9 and theviscosity at 25° C. of the water-soluble eye drop is from about 10 to 70centipoise and, furthermore, the viscosity-average molecular weight ofthe acrylic polymer of the component (b) is from about 2,000,000 to3,000,000 and sodium chloride as the component (c) is contained in theamount of about 0.05 to 0.8% by weight.

8) The water-soluble eye drop according to the above item 1), whereinthe pH of the water-soluble eye drop is from about 4 to 10 and theviscosity at 25° C. of the water-soluble eye drop is from about 5 to 100centipoise and, furthermore, the viscosity-average molecular weight ofthe acrylic polymer of the component (b) is from about 100,000 to3,000,000.

9) The water-soluble eye drop according to the above item 8), whereinthe. pH of the water-soluble eye drop is from about 5 to 9 and theviscosity at 25° C. of the water-soluble eye drop is from about 10 to 70centipoise and, furthermore, the viscosity-average molecular weight ofthe acrylic polymer of the component (b) is from about 2,000,000 to3,000,000.

10) The water-soluble eye drop according to the above item 1), whereinthe component (a) is carteolol hydrochloride.

11) The water-soluble eye drop according to the above item 1), whereinthe component (b) is sodium polyacrylate.

12) The water-soluble eye drop according to the above item 1), whereinthe component (c) is a water-soluble alkali metal salt.

13) The water-soluble eye drop according to the above item 12), whereinthe water-soluble alkali metal salt is sodium chloride or potassiumchloride.

BEST MODE FOR CARRYING OUT THE INVENTION

The component (a) to be mixed with the water-soluble eye drop of thepresent invention is at least one selected from carteolol and an acidaddition salt thereof.

The chemical name of carteolol is5-(2-hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyryl.

The acid addition salt of carteolol includes pharmaceutically acceptableacid addition salts, for example, salts of hydrochloric acid, sulfuricacid, nitric acid, hydrobromic acid, oxalic acid, maleic acid, fumaricacid, citric acid and tartaric acid.

In the present invention,5-(2-hydroxy-3-tert-butylamino)propoxy-3,4-dihydrocarbostyrylhydrochloride (carteolol hydrochloride) is particularly preferred as thecomponent (a).

The component (b) to be mixed with the water-soluble eye drop of thepresent invention is at least one acrylic polymer selected from astraight-chain type polyacrylic acid and a pharmaceutically acceptablewater-soluble salt thereof.

In the present invention, the straight-chain type polyacrylic acid has arepeating unit shown below.

The pharmaceutically acceptable water-soluble salt of the straight-chaintype polyacrylic acid is prepared by neutralizing a carboxyl group ofthe above repeating unit with basic substances, for example, alkalimetal hydroxides such as sodium hydroxide, potassium hydroxide and thelike. The neutralization degree may be any of complete neutralizationand partial neutralization, but complete neutralization is preferred.

The pharmaceutically acceptable water-soluble salt of the straight-chaintype polyacrylic acid is preferably sodium polyacrylate.

The molecular weight of the acrylic polymer as the component (b) is notspecifically limited, but the viscosity-average molecular weight isusually from about 100,000 to 3,000,000, and preferably from about2,000,000 to 3,000,000.

Specific examples of the straight-chain type polyacrylic acid includeAqualic HL-521, AS-52, AS-58 and HL-580 manufactured by Nippon ShokubaiCo., Ltd.; Jurimer AC-10SHP and AC-10LHP manufactured by Nihon JunyakuCo., Ltd.; and A-10H and A-10HL manufactured by TOAGOSEI CO., LTD.Specific examples of the sodium salt of the straight-chain typepolyacrylic acid include Aqualic DL-522, IH-K, IH-L and FH-Kmanufactured by Nippon Shokubai Co., Ltd.; Aronbis S, SS, GL, M and MSmanufactured by Nihon Junyaku Co., Ltd.; A-7100, A-7100G (F), A-20L,A-20LH, A-20P (H), A-20P, A-20PG, A-20P (3) and A-20PX manufactured byTOAGOSEI CO., LTD.; and sodium polyacrylate manufactured by Wako PureChemical Industries, Ltd. During the long-term storage of thewater-soluble eye drop, white turbidity is caused, sometimes, by thekind of additives to be added in the industrial production process ofthe acrylic polymer and residue thereof. Therefore, it is particularlypreferred to use an acrylic polymer which does not cause whiteturbidity.

The component (b) is preferably a straight-chain type sodiumpolyacrylate which does not cause white turbidity of the water-solubleeye drop during the long-term storage, particularly straight-chain typesodium polyacrylate which does not use an additive causing whiteturbidity in the production process, and more specifically Aqualic FH-Kmanufactured by Nippon Shokubai Co., Ltd.

The component (c) to be mixed with the water-soluble eye drop of thepresent invention is at least one selected from a water-soluble alkalimetal salt and a water-soluble amine. The water-soluble alkali metalsalt includes, for example, chloride of alkali metal, carbonate ofalkali metal and alkali metal salt of organic acid. Specific examples ofthe chloride of the alkali metal include sodium chloride, potassiumchloride and the like. Specific examples of the carbonate of the alkalimetal include sodium carbonate, potassium carbonate and the like.Specific examples of the alkali metal salt of the organic acid includesodium acetate, potassium acetate, sodium citrate, potassium citrate andthe like.

The water-soluble amine includes, for example, monoalkylamine,dialkylamine, trialkylamine, monoalkanolamine, dialkanolamine,trialkanolamine and trimethylolaminomethane. Specific examples of themonoalkylamine include methylamine, ethylamine, propylamine and thelike. Specific examples of the dialkylamine include dimethylamine,diethylamine, dipropylamine and the like. Specific examples of thetrialkylamine include trimethylamine, triethylamine, tripropylamine andthe like. Specific examples of the monoalkanolamine includemethanolamine, ethanolamine, propanolamine and the like. Specificexamples of the dialkanolamine include dimethanolamine, diethanolamine,dipropanolamine, dibutanolamine and the like. Specific examples of thetrialkanolamine include trimethanolamine, triethanolamine,tripropanolamine, tributanolamine and the like.

Among the water-soluble alkali metal salts and water-soluble amines, thewater-soluble alkali metal salt is preferred and the chloride of thealkali metal, such as sodium chloride and potassium chloride isparticularly preferred.

In the case of the water-soluble eye drop of the present invention, theviscosity at 25° C. is usually from about 5 to 100 centipoise, andpreferably from about 10 to 70 centipoise. In the present invention, theviscosity of the water-soluble eye drop was measured by using arotational viscometer RE-110SL (manufactured by Toki Sangyo Co., Ltd.).When the viscosity of the eye drop becomes too large, it becomesdifficult to exert the effect as one of the features of the presentinvention, such as ease of handling and affinity to the eyes (feeling inthe case of dropping it in the eyes). To the contrary, when theviscosity of the eye drop becomes too small, the duration time of drugefficacy is liable to be reduced.

The amount of the component (a) to be mixed with the water-soluble eyedrop of the present invention is usually from about 0.1 to 5% by weight,and preferably from about 0.5 to 3% by weight.

The amount of the component (b) to be mixed with the water-soluble eyedrop of the present invention is usually from about 0.3 to 10% byweight, and preferably from about 0.3 to 0.5% by weight. The amount ofthe component (b) varies depending on the viscosity-average molecularweight of the acrylic polymer to be used, but it is preferably mixed sothat the viscosity at 25° C. of the resulting water-soluble eye drop iswithin a range from 5 to 100 centipoise as mentioned above.

The component (c) is mixed with the water-soluble eye drop of thepresent invention so that the concentration in the eye drop is usuallywithin a range from about 10 to 140 mmol, and preferably from about 30to 120 mmol. The component (c) is used to enhance the solubility of thecomponent (b) in water, but it also serves as an isotonicity. In thepresent invention, the component (c) is preferably used in the amountenough to make the eye drop isotonic when the component (c) is combinedwith the component (a). Such an amount varies depending on the kind ofthe component (c) and can not be decided completely. For example, in thecase of sodium chloride, the amount is usually from about 0.05 to 0.8%by weight, and preferably from about 0.2 to 0.54% by weight. When theother isotonicity such as D-mannitol is further mixed, together with thecomponent (c), the amount of the component (c) can also be reducedaccording to the amount of the isotonicity.

The eye drop of the present invention is produced, for example, bymixing a predetermined amount of the above components (a) to (c) withsterile distilled water as a base and subjecting the solution to asterilization treatment.

It is possible to further mix isotonicities, buffering agents, pHadjustors, solubilizers, stabilizers, antioxidants and antiseptics withthe eye drop of the present invention.

The isotonicity includes, for example, a conventionally known one suchas D-mannitol, glucose and glycerin.

The buffering agent includes, for example, a conventionally known onesuch as sodium dihydrogen phosphate, sodium hydrogen phosphate,potassium dihydrogen phosphate, potassium hydrogen phosphate, boricacid, sodium borate, citric acid, tartaric acid and sodium tartrate.

The pH adjustor includes, for example, a conventionally known one suchas acid (e.g. hydrochloric acid, acetic acid, etc.) and base (e.g.sodium hydroxide, potassium hydroxide, etc.).

The solubilizer includes, for example, a conventionally known one suchas polyoxyethylene glycol ethers (e.g. sodium carboxymethylcelullose,polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, etc.),polyethylene glycol higher fatty acid esters (e.g. polyethylene glycolmonolaurate, polyethylene glycol monooleate, etc.) and polyoxyethylenefatty acid esters (e.g. polyoxyethylene sorbitan monolaurate,polyoxyethylene sorbitan monooleate, etc.).

The stabilizer includes, for example, a conventionally known one such ashydroxypropylmethylcellulose, polyvinyl alcohol, carboxymethylcellulose,hydroxyethylcellulose, glycerin and EDTA.

The antioxidant includes, for example, sodium bisulfite, sodiumthiosulfate and ascorbic acid.

The antiseptic includes, for example, a conventionally known one such aschlorobutanol, benzalkonium chloride, cetylpyridinium chloride,thimerosal, phenethyl alcohol, methyl paraben and propyl paraben.

The pH of the water-soluble eye drop of the present invention is usuallyfrom about 4 to 10, and preferably from about 5 to 9. When the pHexceeds 10, there is a fear that the component (a) is deposited in theeye drop of the present invention. On the other hand, when the pH issmaller than 4, there is a fear that the component (b) is deposited inthe eye drop of the present invention.

It is preferred that the water-soluble eye drop of the present inventionand lacrimal fluid are isotonic. The water-soluble alkali metal salt asthe component (c) of the present invention serves as an isotonicity, andvarious isotonicities described above may be further mixed. It isparticularly preferred that the pH of the water-soluble eye drop of thepresent invention is adjusted within a range from about 5.5 to 8.5, andpreferably from about 6.5 to 7.5.

The water-soluble eye drop of the present invention is used in the samemanner as that in the case of a conventionally known eye drop. Forexample, the water-soluble eye drop is preferably dropped in the eyesfrom a suitable eye drop container, or sprayed the eyes using a sprayingdevice.

EXAMPLES

The following Examples further illustrate the present invention in moredetail. In the following Examples, percentages are by weight unlessotherwise stated.

Preparation Example 1

Carteolol hydrochloride   2% Sodium polyacrylate 0.4% Sodium chloride0.2% D-mannitol   2% Sterile distilled water 95.4%  Total 100% 

A 0.8% sodium polyacrylate solution was previously prepared by adding0.8 g of a straight-chain type sodium polyacrylate [trade name: AronbisMS manufactured by Nihon Junyaku Co., Ltd., viscosity-average molecularweight: 2,000,000 to 3,000,000] to 99.2 g of an aqueous sodium chloridesolution, which is obtained by dissolving 0.4 g of sodium chloride in98.8 g of sterile distilled water, and dissolving the straight-chaintype sodium polyacrylate using a stirrer.

Two (2) g of D-mannitol was added to 40 g of an aqueous solution ofcarteolol hydrochloride prepared in the concentration of 5% anddissolved using a stirrer and, after confirming that D-mannitol wassufficiently dissolved, 50 g of the 0.8% sodium polyacrylate solutionprepared previously and 8 g of sterile distilled water were added. Theywere dissolved by sufficiently stirring to obtain a water-soluble eyedrop (preparation No. 1) of the present invention.

The pH of the resulting water-soluble eye drop was 8.0 and the viscosityat 25° C. was 20 centipoise.

The pH was measured by using a pH meter (HORIBA, pH meter M-8AD). Theviscosity was measured at 25° C. by pouring 1-1.2 ml of the abovewater-soluble eye drop into a sample cup, using a rotational viscometerRE-110SL (manufactured by Toki Sangyo Co., Ltd.).

Comparative Preparation Examples

Various eye drops (preparation Nos. 2 to 11) were produced by mixingcarteolol hydrochloride, water-soluble polymer compounds shown in Table1 below, sodium chloride and other additives (isotonicity, bufferingagent and pH adjustor) in a predetermined amount in accordance with theabove Preparation Example. In Table 1, percentages are by weight basedon the preparation, and “mM” means a millimolar concentration of sodiumchloride based on the preparation.

The measurement results of the pH and viscosity at 25° C. of these eyedrops are shown in Table 1.

TABLE 1 Others (isotonicity, Prepa- Carteolol Water-soluble Sodiumbuffering agent, Viscosity ration No. hydrochloride polymer compoundchloride pH adjustor) pH (cps) 1 2% Sodium poly- 0.2% D-mannitol 2% 8.020 acrylate 0.4% (34.2 mM) 2 2% No addition of 0.54% 5 mM-phosphate 6.71 polymer (control) (92.4 mM) buffer solution 5 mM 3 2% Sodium poly- —D-mannitol 2.5% 8.3 14 acrylate 0.9% 4 2% Sodium poly- — D-mannitol 2.5%6.7 12 acrylate 0.9% Hydrochloric acid (q.s.) 5 2% Sodium dextran —D-mannitol 2% 6.7 24 sulfate 5% 6 2% Sodium poly- — D-mannitol 2% 7.0 43styrene sulfonate 5% 7 2% Potassium poly- — D-mannitol 1.9% 6.7 20 vinylsulfate 5% 8 2% Sodium chondroitin — D-mannitol 1.2% 5.8 33 sulfate 5% 92% Sodium hyaluronate — D-mannitol 3.1% 5.9 23 0.2% 10 2% Sodiumhyaluronate D-mannitol 3.1% 5.9 27 0.3% 11 2% Carboxyvinyl 0.52% Sodiumhydro- 5.0 113 polymer (cross- (90 mM) xide (q.s.) linked type) 1.25%

The water-soluble polymer compounds listed in Table 1 are as follows.

Sodium polyacrylate mixed with the preparations No. 3 and No. 4: tradename “Sodium Polyacrylate” manufactured by Wako Pure ChemicalIndustries, Ltd., viscosity-average molecular weight: about 250,000 toabout 750,000.

Sodium dextran sulfate mixed with the preparation No. 5: trade name“DS-500” manufactured by Meito Sangyo Co., Ltd., viscosity-averagemolecular weight: about 500,000.

Sodium polystyrene sulfonate mixed with the preparation No. 6: tradename “PS-100” manufactured by TOSOH CORPORATION, viscosity-averagemolecular weight: about 1,100, 000.

Potassium polyvinyl sulfate mixed with the preparation No.7: trade name“Potassium Polyvinyl Sulfate” manufactured by Wako Pure ChemicalIndustries, Ltd., viscosity-average molecular weight: about 240,000.

Sodium chondroitin sulfate mixed with the preparation No. 8: trade name“Sodium Chondroitin Sulfate for “SEIKAGAKU” for injection”manufacturedby SEIKAGAKU CORPORATION, viscosity-average molecular weight: about40,000.

Sodium hyaluronate mixed with the preparation No. 9: trade name“Hyaluronic Acid HA-QSS” manufactured by Kewpie Co., Ltd.,viscosity-average molecular weight: about 2,800,000.

Sodium hyaluronate mixed with the preparation No. 10: trade name“Hyaluronic Acid HA-Q” manufactured by Kewpie Co., Ltd.,viscosity-average molecular weight: about 1,150,000.

Carboxyvinyl polymer mixed with the preparation No. 11: trade name“Noveon AA1” manufactured by BF Goodrich Co.

Preparation Example 2

According to the same manner as that described in Preparation Example 1except for using sodium polyacrylate [trade name: Aqualic FH-Kmanufactured by Nippon Shokubai Co., Ltd., viscosity-average molecularweight: 2,000,000 to 3,000,000] as the straight-chain type sodiumpolyacrylate, a water-soluble eye drop (preparation No. 12) of thepresent invention was obtained.

The pH of the resulting water-soluble eye drop was 8.0 and the viscosityat 25° C. was 20 centipoise.

Experiment Example 1

Using various eye drops (preparations No.1 to No. 11) obtained above,the concentration (ng/ml) of the drug (carteolol hydrochloride) in theaqueous humor of house rabbit was determined in accordance with thefollowing method.

That is, a white rabbit was fixed to a fixing device, and various eyedrops (50 μl each) were dropped in both eyes. Four and eight hours afterdropping in the eyes, the white rabbit was slaughtered by injectingbarbital. The eye ball surface was washed with an isotonic sodiumchloride solution and the aqueous humor was extracted, and then theconcentration of the drug (ng/ml) in the aqueous humor was measured byreversed phase HPLC. The concentration of the drug in the aqueous humorof the house rabbit after 4 hour and 8 hours have passed since the eyedrop was dropped in the eyes are shown in Table 2.

TABLE 2 Concentration of drug in aqueous humor after dropping eye dropin the eyes (ng/ml) Preparation No. After 4 hours After 8 hours 1 20781127 2 361 52 3 1415 405 4 1298 177 5 596 — 6 333 — 7 514 — 8 688 — 9672 — 10 699 —

The followings are apparent from Table 2.

In the case of a control (preparation No. 2) wherein the water-solublepolymer compound is not mixed, the concentration of the drug in theaqueous humor after 4 hours have passed since the eye drop was droppedin the eyes is 361 ng/ml, whereas, in the case of the eye drop(preparation No. 1) of the present invention, the concentration of thedrug in the aqueous humor after 4 hours have passed since the eye dropwas dropped in the eyes is 2078 ng/ml, that is, the concentrationincreased by about six times. On the other hand, in the case of the eyedrops (preparations No. 3 to No. 10) of the Comparative Examples, theconcentration of the drug in the aqueous humor after 4 hours have passedsince the eye drop was dropped in the eyes increased by about 1-4 timescompared with the control.

After 8 hours have passed since the eye drop was dropped in the eyes,the drug concentration was very high in the case of using the eye drop(preparation No. 1) of the present invention, and was superior induration of drug efficacy.

The data in the case of using the preparation No. 11 is not shown inTable 2, but it was confirmed that the preparation No. 11 is inferior induration of drug efficacy.

Preparation Example 3

The water-soluble alkali metal or water-soluble amine shown in Table 3below was added to carteolol hydrochloride and sodium polyacrylate[trade name: Aronbis MS manufactured by Nihon Junyaku Co., Ltd.,viscosity-average molecular weight: 2,000,000 to 3,000,000], followed bymixing in a rotator for about 12 hours. Thereafter, clarity and color ofthe solution were visually confirmed. Carteolol hydrochloride and sodiumpolyacrylate were used in such an amount that the concentration ofcarteolol hydrochloride and that of sodium polyacrylate in the eye dropare 2% and 0.5%, respectively. The water-soluble alkali metal salt orwater-soluble amine was used in such an amount that the resulting eyedrop is nearly isotonic. In Table 3, the concentration of thewater-soluble alkali metal salt or water-soluble amine to be added isrepresented by “percentage” and “mM”.

The pH of the resulting various eye drops is also shown in Table 3.

TABLE 3 Concent- Concent- ration (%) ration (mM) Solubility pH Sodiumchloride 0.54 92.4 dissolved 7.77 Sodium citrate 1.92 65.3 dissolved7.87 Sodium acetate 1.39 102.1 dissolved 7.87 Potassium chloride 0.79106.0 dissolved 7.86 Potassium acetate 1.00 102.0 dissolved 8.24 Tris*1.21 99.9 dissolved 9.50 Sodium carbonate 0.92 32.2 dissolved 7.36*Tris: Tris(hydroxymethyl)aminomethane

Since sodium carbonate was not dissolved in the eye drop by the aboveoperation, the pH was lowered to about 7 (i.e. pH=7.36) by furtheradding hydrochloric acid, thereby making it possible to dissolve in theeye drop.

Preparation Example 4

According to the same manner as that described in Preparation Example 1except for using sodium polyacrylate [trade name: Aqualic FH-Kmanufactured by Nippon Shokubai Co., Ltd., viscosity-average molecularweight: 2,000,000 to 3,000,000] as the straight-chain type sodiumpolyacrylate, a water-soluble eye drop of the present invention wasobtained.

Carteolol hydrochloride 2% Sodium polyacrylate 0.5% Sodium chloride 0.5%Sterile distilled water q.s. Total 100%

Preparation Examples 5 to 13

To the formulation of Preparation Example 4, each of the followingvarious additives was added in each amount to obtain each water-solubleeye drop (nine kinds) of the present invention.

Sodium citrate: 0.006 M, 0.06 M Citric acid: 0.0057 M Polyvinyl alcohol:0.1%, 0.2%, 0.4%, 0.8%, 1.0% Tris(hydroxymethyl) 0.01 M aminomethane

Test of Dissolution State

The respective water-soluble eye drops obtained in Preparation Examples4 to 13 were observed during the storage at room temperature for 6months. As a result, all preparations were transparent and any change inclarity and color of the solution could not be recognized.

Industrial Applicability

The water-soluble eye drop of the present invention has a remarkablylong duration time of drug efficacy, and is superior in intraocularpressure inhibition action and is effective for treatment of glaucoma.

The disclosure of Japanese Patent Application Serial Nos.9-353039 and10-298550, filed on Dec. 22, 1997 and Oct. 20, 1998, respectively, areincorporated herein by reference.

What is claimed is:
 1. A water-soluble eye drop composition comprising(a) at least one selected from the group consisting of carteolol and anacid addition salt thereof, (b) at least one acrylic polymer selectedfrom the group consisting of a straight-chain type polyacrylic acid anda pharmaceutically acceptable water-soluble salt thereof, and (c) atleast one selected from the group consisting of a water-soluble alkalimetal salt and a water-soluble amine.
 2. The water-soluble eye dropaccording to claim 1, wherein the component (a) and the component (b)are contained in the amount of about 0.1 to 5% by weight and the amountof about 0.3 to 10% by weight, respectively, and the concentration ofthe component (c) is from about 10 to 140 mmol.
 3. The water-soluble eyedrop according to claim 2, wherein the pH of the water-soluble eye dropis from about 4 to 10 and the viscosity at 25° C. of the water-solubleeye drop is from about 5 to 100 centipoise and, furthermore, theviscosity-average molecular weight of the acrylic polymer of thecomponent (b) is from about 100,000 to 3,000,000.
 4. The water-solubleeye drop according to claim 3, wherein the pH of the water-soluble eyedrop is from about 5 to 9 and the viscosity at 25° C. of thewater-soluble eye drop is from about 10 to 70 centipoise and,furthermore, the viscosity-average molecular weight of the acrylicpolymer of the component (b) is from about 2,000,000 to 3,000,000. 5.The water-soluble eye drop according to claim 2, wherein the component(a) and the component (b) are contained in the amount of about 0.5 to 3%by weight and the amount of about 0.3 to 0.5% by weight, respectively,and the concentration of the component (c) is from about 30 to 120 mmol.6. The water-soluble eye drop according to claim 5, wherein the pH ofthe water-soluble eye drop is from about 4 to 10 and the viscosity at25° C. of the-water-soluble eye drop is from about 5 to 100 centipoiseand, furthermore, the viscosity-average molecular weight of the acrylicpolymer of the component (b) is from about 100,000 to 3,000,000.
 7. Thewater-soluble eye drop according to claim 5, wherein the pH of thewater-soluble eye drop is from about 5 to 9 and the viscosity at 25° C.of the water-soluble eye drop is from about 10 to 70 centipoise and,furthermore, the viscosity-average molecular weight of the acrylicpolymer of the component (b) is from about 2,000,000 to 3,000,000 andsodium chloride as the component (c) is contained in the amount of about0.05 to 0.8% by weight.
 8. The water-soluble eye drop according to claim1, wherein the pH of the water-soluble eye drop is from about 4 to 10and the viscosity at 25° C. of the water-soluble eye drop is from about5 to 100 centipoise and, furthermore, the viscosity-average molecularweight of the acrylic polymer of the component (b) is from about 100,000to 3,000,000.
 9. The water-soluble eye drop according to claim 8,wherein the pH of the water-soluble eye drop is from about 5 to 9 andthe viscosity at 25° C. of the water-soluble eye drop is from about 10to 70 centipoise and, furthermore, the viscosity-average molecularweight of the acrylic polymer of the component (b) is from about2,000,000 to 3,000,000.
 10. The water-soluble eye drop according toclaim 1, wherein the component (a) is carteolol hydrochloride.
 11. Thewater-soluble eye drop according to claim 1, wherein the component (b)is sodium polyacrylate.
 12. The water-soluble eye drop according toclaim 1, wherein the component (c) is a water-soluble alkali metal salt.13. The water-soluble eye drop according to claim 12, wherein thewater-soluble alkali metal salt is sodium chloride or potassiumchloride.